Hello from MRSI 2022. We are excited for this presentation, our live debate for fertility and sterility. Welcome everyone, both in person and live and virtual.
We're excited for what's to come. I want to introduce our moderators. We have Pietro Bortoletto and Eve Feinberg here.
Pietro's almost done with fellowship. Almost. Days.
How many days? 13 days, six hours. So he is leaving Cornell, moving on in his career to Boston IVF, and then we have Eve Feinberg here from Northwestern. We are excited for this pro versus con debate, and I won't tell you yet who's going to win.
Thank you, Amber, and welcome everyone, both here at the Midwestern Reproductive Symposium International and joining us online to the Fertility and Sterility Journal Club Global. It's always a pleasure to be back in Chicago. We've done this event now for several years running, so thank you again for the invitation to be here.
Today we have the privilege of talking about a paper that's coming out in Fertility and Sterility entitled The Evidence for Effectiveness of Immunological Therapies in Women with Subfertility and or Undergoing ART. It's a great paper written by Pedro Melo and the team at Tommy's in the UK that I think has really done a nice job of going through the evidence for and against some of these immunologic therapies that we commonly use in our practice. Before we get started into the debate, I want to introduce my co-host, Dr. Eve Feinberg, who is the fellowship director and associate professor at Northwestern University and will be helping me co-moderate today's event and will also introduce our panel.
Great. Thanks so much, Pietro. It is a distinct pleasure to be here and many thanks to Angie Baltos for inviting us all to do Fertility and Sterility Journal Club.
On our panel we have two sides. We have the pro side that is arguing for pro-immunologic therapy and that is Steve Young from the University of North Carolina Chapel Hill and Scott Nelson from the University of Glasgow. And to my left we have the con side that is Richard Scott from RMA.
We have Amber Cooper from KindBody and Megan Sachs, who's a fellow, first-year fellow at the University of Cincinnati. So who's going to win? And we should preface this with saying that we're asking people to debate a stance that they may not necessarily agree with. So they were randomly selected to sit on the side of the stage.
So we'll place that caveat in a little bit of coverage for whatever outlandish position our panelists decide to take. The format for the panel today will be a opening statement just like you hear in a court case. Everyone's going to have an opportunity to give us two-minute spiel on why they think their side is right and then we'll transition to an open debate where they're going to hopefully go at each other and pick apart the evidence that they're using to support their claims.
At the end we will have a couple of minutes for question and answer. So if there are questions from the audience we'll take them and we'll be able to hopefully come up with a consensus agreement from the audience here at MRSI on which side won. So without further ado I think we should just go ahead and get started.
I'm going to turn the mic over to Dr. Young who's going to tell us a little bit about why he thinks we should all be using immunologic therapies in the subfertile or ART population. Okay well I think we need to take a step back and understand the biology. You know the endometrium has a dynamic and complex stew of cytokines and there are changing immune cells throughout the cycle.
There are both lymphoid and myeloid cells. These cells are important for angiogenesis. They're important for menstruation.
They're important for implantation and tissue remodeling and all these things are critical for reproduction. Leukocytes make up to 30 percent of the total number of cells in the endometrium at certain times in the cycle. And furthermore the numbers of these cells what they produce and their cell surface phenotype is dramatically altered by progesterone and estradiol.
So they're cyclically regulated and in fact if you look with an evolutionary lens what you see is that when mammals start gaining placentas and when they get a true placenta the the eutherians what you see is the progesterone regulated genes suddenly shift and incorporate immune cytokines for regulation. And so there's this evolutionary clear factor that that immune molecules are involved in placentation and then there's our observations. Time and again animal models have shown that if you alter the immune system you get reproductive failure.
Just as an example if you alter on the early embryo a one complement regulatory factor that's one factor that that protects against complement attack you get a hundred percent fetal embryonic resorption. You get a hundred percent pregnancy loss. That's just one of many of these immune models in mice and in other animals.
I've had patients that have a clear immunologic phenomena just occurring during pregnancy it disappears when they're no longer pregnant. I think it's then it's undeniable that the immune system plays a role in the establishment and maintenance of pregnancy. And if that's true it's inconceivable that this large evolutionarily recent dynamic and complex immune milieu doesn't sometimes go wrong.
And so I think that we have to consider immune therapies in reproductive failure. All right what a start. All right so go ahead Dr. Sacks.
I always love putting the the very senior professors with the junior hungry fellows who have also read the literature. Dr. Sacks why should we not be using immune therapies? Thank you so much. Let me just start off by saying incredible opportunity so excited to be a part of this panel today.
We are one of the most evidence-based fields. I feel that providers in this field are willing to change their practice based on the most up-to-date evidence reproducible literature. And with that in mind we have to keep in mind this meta-analysis systematic review these authors Dr. Malow and colleagues have gone to so much trouble to demonstrate that the evidence is just not there yet.
When you look at the heterogeneity among these studies it's so large that I think back to one of my mentors who said before you can really successfully create an argument you have to argue that other side first. And when I try to look into this how can I make an argument for pro looking at perhaps the autoimmune population and seeing that that heterogeneity among those few there's about five studies included here that even within that population we're including less than 100 patients in the treatment arm. We can't draw a conclusion from this and I am also obliged to ask Dr. Young in response if you're willing to share with the audience here how many times have you prescribed prednisone to patients which you may have shared at this conference within the last week.
I don't think the fifth amendment is allowed on stage in a debate. This is a lawless stage. We're not arguing amendments this weekend.
I can tell you a success story of using prednisone if you'd like. I had a patient not too long ago a couple years ago who came to me and we were discussing her recurrent pregnancy loss and I said have you had any kind of immune disease before. She said you know a number of years ago they thought I might have rheumatoid arthritis but the symptoms went away.
And I said well what happens when you get pregnant. Anything different. She goes you know I get this rash.
I said you have it now. No no it goes away whenever I have my miscarriage. She'd had about six or seven maybe eight miscarriages.
And I said huh. And we talked and there were no other. We ruled out other things.
And I said you know let's try some prednisone and see what happens. And she now has a child as a result. And so let's try some prednisone and see what happens.
How many of us have been accused of that. But I think our patients probably demand a little bit stronger evidence base. So now that Dr. Sachs has had an opportunity to argue the con I'm going to let Dr. Nelson maybe shore up that let's try some prednisone and see what happens argument.
Okay so the other side of this debate are going to try to change the title of the paper to lack of evidence for the effectiveness of immunological therapies. But the reality of it is are the patients when you read this paper did it actually change your practice. Think about it.
Did you do anything and change in the back of this. I probably think not. And the reason why and I realize this is a global audience but it's mainly in the U.S. because are these represented of your U.S. population.
There's 53 studies in this meta-analysis. Seven are from the U.S. They are essentially from 1994 to 2008. Yeah in terms of that.
So 1994, 95, 97, 98. Were you born. Yeah just barely.
Barely exactly. So the reality is that clinical medicine that you practice today is not like what we're doing in these in reality. So it talks a lot about aneuploidy within the context of this paper.
But if you take the time and effort to go through all those 53 studies not a single one of them examines euploid embryos. And Dr. from the RMA and Dr. Scott's group have shown that actually if you have three euploid embryos you're going to get to 93 percent. And then it's so it's this small subgroup that are not even in this paper that actually we're probably talking about that which you know Dr. Young has said is going to be a benefit for you.
And then last when you think about the heterogeneity of these studies. So let's just if you look at some of those point estimates and the two biggest point estimates are for intrauterine GCSF. The reality is that those are driven by you know one study.
For example, let's give an example. Calum was looking at adhesions and then wanted to put some gel in in terms of being able to look at the effects of that on the endometrium. In contrast to the Mueller trial, so the Calum trial, where it was actually just some HCG installation on the day of trigger.
So how can you put a gel after hysteroscopic resection of adhesions together along with you know a Calum paper which was HCG. So when we talk about the heterogeneity of these studies the reality is that it's all put back together and actually you can't say you can't take that meta-analysis and say okay this is what we believe for that population. You actually have to go and look at the individual studies.
And not only that, you then think okay what other evidence is there around. So I know Ari Kumasari really well. He's from the UK.
Ari does these meta-analysis. He's got a whole pipeline and it's normally to fund this next big grant. And Ari's published in the New England Journal of Medicine.
We've got another big one you know trial coming through just now. But that's what drives these. So he can do that kind of primary point estimate for the big grant that's going to get three million pound grant to fund these.
But at the same token just 50 miles away if you look at the intralipids they've got two RCTs. Siobhan Quimby who many of you will know is a person who coined natural killer cells in terms of thinking about recurrent miscarriage also did a meta-analysis published in 2021. She's got five RCTs in hers.
So here's two groups you know both working for Tommy's. Both with Tommy's funding. One's got two RCTs in their meta-analysis which is presented here.
Another one's got five. Who do you believe? And actually if you look at the intralipid one which is the bigger point estimates and perhaps more accuracy on it you know the confidence interval is the point estimate is 1.83 for intralipids with confidence intervals of 1.16 to 2.07 for clinical pregnancy. And you don't need to follow up live birth because clinical pregnancy is super correlated with you having live birth.
So the reality is although the opposing team will say this is a lack of evidence actually what you need to think about is that any of these studies relevant to your population and what I think we'll be able to show you very clearly is there's some very clear examples when this does become relevant to you and you may benefit from using these appropriate therapies. Dr. Cooper is there evidence to suggest that any of these things work? There is a tremendous amount of evidence to say that the immune system matters. I think we all probably would agree to that and I think that we know that you need enough of an immune system for implantation to occur but not too much to put it simply.
And I find it interesting when we do treatments that almost combine these principles right like oh let's do a scratch test to try to improve the immune cells coming in but let's give them immunomodulatory therapies to push away the immune system. We don't even understand the why. So I think there's a tremendous amount of evidence to say the immune system matters and I really do believe that.
The problem is we have a big access to care issue in the U.S. and globally where we have patients that can't afford multiple cycles of IVF nor PGT and want to do everything because they are a very vulnerable patient population. And we do things because we think first do no harm, right? But the question here is is there evidence to say that the current immune therapies are effective, right? And the answer is no. The problem is we need to go backwards.
We need to define who which we haven't. We haven't even defined recurrent implantation failure as Dr. Young taught us you know yesterday. We barely have defined recurrent pregnancy loss and we don't really even understand that.
We are getting better at understanding there is a small subset of patients that probably would benefit from these things but the tests what does a positive ANA mean? Natural killer cells. You know we there is very clear evidence that the natural killer cells in the blood are very different than those in the uterus. We don't understand how intralipids even work and there are risks of giving something like that.
So we have to understand the who, we have to understand the what, and we have to understand how we're going to manage these tests that don't even make sense. So bottom line is is there evidence to support the effectiveness of the current immunologic therapies? The answer is no. Dr. Beltzos.
Socrates said the one thing that is true and the one thing about knowledge is that if you are really really smart you know that you know nothing. What does that mean here? The immune system is so complex and there are so many variables. It is very challenging to eliminate all the variables in order to make strong conclusions.
And I think when we look at these therapies and we've all taken care of the patients that have pretty healthy lining is 11 millimeters trilaminar euploid AA and your transfer was all net nothing. And then you get this squeaky little morula it's her last covered cycle the lining's five millimeters it's got fluid and it implants and you get a baby. Like what do we know and why do these recurrent failures occur? And I try to put things into three buckets either it's something with the embryo that was wrong if you will something's wrong with the embryo something's wrong with the uterus or the body receiving it or a third was bad luck.
There is no real negative pathology of the embryo or the lining or the immune system. But when you're looking at recurrent failure one of the things is to wait for RCT but that might take now we've I've been doing this a few years how long have we been doing this? And we keep talking about this since I was a fellow why how the immune system interacts and so we're faced with one scientific knowledge two making conversations around the clinical practice based on this knowledge and three Mrs. Smith who's sitting in front of you right? So those are the forces that as we talk as professors and as we talk as the doctor of that patient and so I do believe that we do the best we can with evidence-based medicine but as Socrates says we really don't know a lot about what this means we don't know what causes labor we don't know what causes puberty and we don't know what causes RIF or recurrent implantation failure RIF. Dr. Scott what do we know? Well we know that none of the therapies work right I mean that's always one of the the most clever things you can do and for those of us on the con side we look at the pro side there's a lot of intellectual horsepower over there so this is a tough task for us but the reality is they're trying to reframe the question.
The question isn't whether the immune system is important as Amber said the question is whether or not these therapeutics are provide benefit to our patients and quite frankly this literature is a disaster. It's not been well done it is very small numbers of patients and if you had a particular history like someone who really sounds like they have a progesterone allergy you might want to immunosuppress them but how many of those do you see a day right per day in your clinic probably not all that many and so the reality is that's not that's not the essence of what this is. Intralipid is a great example you can go through all the different therapies people study intralipid pro or con do they control for those studies for whether they got propofol for their sedative agent no you know that that white stuff that they give to our patients to make them fall asleep and wake up guess what it's diluted in intralipid.
So what percentage of the patients in those studies probably got intralipid probably 100 percent or very near and and so the reality is we we have to be much more systematic. We we also don't know there's no dose ranging studies there's no duration of treatment study there's no good study saying it has to begin before a certain time or end at a certain time because an inflammatory state in the uterus doesn't resolve in a minute. Do you have to start weeks or months before what would be effective.
Everybody agrees the immune system is important and I would go so far as to say that most of us would agree that it must break sometime. It must be part of what goes wrong for our patients but we have no adequate diagnostic tests. Everything that's been proposed has been resoundingly demonstrated and unfortunately not to be prognostic and none of these therapies the peripheral monocytes and maybe the intrauterine GCSF notwithstanding with very small somewhat compromised studies just haven't been shown to be of benefit and they're expensive and they have risks and since everyone else has used an anecdote I'll use one because this this area of science seems to to generate an almost religious fervor.
So I had a patient a long time ago this is 20 years ago who came to our clinic it failed a bunch of times and and and we we got lucky and got her pregnant. I did not know that on the side she was seeing a an individual subspecialty certified in recurrent loss. Now she'd never had a recurrent loss she just never had implanted before and it turns out she was on aspirin and prednisone and IVIG and a bunch of other stuff.
I won't bore you with what when she was 11 weeks pregnant she got septic. She spent nine days in the ICU lost the pregnancy and the rest of her life she rides around on one of those little scooters with oxygen in her nose because she had significant pulmonary fibrosis for being intubated for over a week. So she came back to the clinic having already identified a gestational carrier that she wanted to use to transfer some of her remaining embryos and she was so excited because she had had the carrier screened the carrier had the same immunologic abnormalities and was going to need all those same therapies.
This is somebody who's had two normal pregnancies before. There's way too much passion in this. There's way too little science in this and we need to step back and say we should not be doing these things until there's a higher level of evidence.
If you are a true believer great. If you are a sophisticated immunologist and you want to bring some sanity into this world great. Get an IRB, do a study, carefully identify your patients and characterize them for the rest of us and teach us important lessons.
But for now there's no place to go with any of these treatment modalities that's really in the the frame of acceptable routine practice. Do you want to rebut to that or should I ask my next question? Here it comes. So Richard's absolutely right.
You know I think there's often this assumption that you know you'll do something and it'll have no harm effect and what you've identified is that there can be harm and the meta-analysis will show for example for recurrent you know leukemia inhibitor factor actually the odds ratio was moved to the left and that there was evidence of harm. So Richard has very you know eloquently elucidated kind of the pathway to coming up with better studies. But let's take aspirin.
So in terms of aspirin it is essentially recommended that you know if you've got an increased risk of pre-eclampsia you can reduce that risk by giving aspirin. What these studies show actually aspirin is very safe but what we realize is that implantation of you know the risk of pre-eclampsia is actually set up long before the 12 weeks that's often recommended in you know the National Institute of Clinical Excellence, the NICE guidelines are in the UK where you've got BMI above 30 or you've got a previous you know any risk factors for pre-eclampsia you know you'd be getting 75 milligrams. Kipros Nicolaides and colleagues you know from the Fetal Medicine Foundation have very nicely shown that that's probably a suboptimal dose and also it should be started earlier.
So we in terms of not necessarily aspirin here but actually not thinking about immunological therapies but perhaps other diseases that are not even being considered in the context of this which are much more relevant and much more prevalent you know think about about five percent of the population are going to have hypertension diseases and causes the associated perinatal morbidity with that. Actually perhaps we should be considering aspirin not because of RIF or any of these other things but because of the wider world that we operate in in terms of trying to ensure that people have a healthy family. Well I just I just want to actually support your statement in general but say even that is not quite that simple.
A couple a couple of reasons but the main one is that there was a five-center NIH sponsored and monitored study giving aspirin to people throughout pregnancy and there was an increased risk of abruption. It's and and John Health wrote that paper really out really outstanding. Now I don't think that there's great morbidity in fact when patients ask me if they can take aspirin I generally tell them probably reduces their risk of heart disease when they're 80 but I'm not sure it's going to do a whole lot for their for their pregnancy.
I don't really think it's that pathologic and I don't want to exaggerate and be accused of hyperbole but I wouldn't say there's no risk either but across the board it's one thing to say you can take aspirin if you want we all know that's a relatively benign thing to do. It's another thing to charge patients many thousands of dollars for therapies which have really never really have no evidence are beneficial and quite frankly all that that great theory about how it changes the immune system and might be helpful even the physiologic basis for those for those interventions are not well demonstrated. The fact that you can knock something out in a mouse and break something is by no means relevant to the human condition unless you've got a person who just happens to have a mutation in that gene that creates a knockout but of course that mouse was sterile and that person's here so it's probably not the case and so that you know it's very difficult to project beyond data both in animal models and in the human model so I think I think we have to be careful.
I think the question that I want to ask and I'm going to start with Dr. Beltzos maybe Socrates can help us here but who I'm going to channel him who deserves an evaluation and at what point and I'd like each of the panelists on the pro side to answer that question. Can you add what's in the evaluation? So who deserves an evaluation? What is in the evaluation and when do you do the evaluation? So I think with looking at the data of success with a euploid FET single transfer and if that's been done two to three times without success and without any other evidence of issues an example of other evidence of issues you might suspect that on one of her ultrasounds recently you saw some fluid maybe there's a hydro maybe you want to go back and do an HSG on her that's an example but if everything is looking good I would say one to two failed euploid transfers are times where we want to start talking about making sure we're not missing something else now what are the missing something else's and how does that impact things we've talked about autoimmune conditions infections these mock cycles are you timing progesterone correctly is there evidence of chronic endometritis that has not been evaluated endometriosis that is causing inflammation and again HSG for hydros an old old study was showing that bilateral self injectomy for euploid transfer for failed transfers increased pregnancy rates because probably some of those people you've missed hydros was there something else nope so Dr. Young when would you begin so I want to get at the differences in timing of when we do this evaluation and is there a standard definition the other one that we struggle with are those let's say poor responders they've done multiple cycles of IVF in hopes to get more embryos to have their two to three children and in the end they only have one precious embryo to try with before they move on to donor egg and and in those cases before you use that precious embryo we talk also about although you also mentioned that you don't want to chase problems that don't exist you also don't want to monday morning quarterback tell her well we could have should have tested you for xyz and you actually find out she has a problem and you missed it so you're saying before euploid transfer one possibly after euploid transfer one possibly after two euploid or possibly after three euploid Dr. Young what's your depending tailored to the patient Dr. Young what do you think this is specifically for immunologic evaluation yes you're concerned a patient has an immunologic condition that warrants therapy which you have suggested you were for yeah when would you evaluate them uh is this truth or is this uh no this is for the debate for the debate it is it is imperative I just want to remind him his fellows are watching I just don't want to okay while he's thinking so the in reality what we see was the population has shifted over the years you know the people in this room are old enough to know that actually they were doing it after you know three failed transfers you know if you put it in the context of the UK about three three percent of cycles have pgta three percent so you can imagine that if you're putting back untested embryos the population that you think have recurrent implantation failure is absolutely massive and Richard and I were talking the other day because actually that was a landmark paper for me which is that to be replicated but showed that actually you've got three euploid embryos you should be at 92 percent and that leaves another 92.3 you think it is with some confidence in those around about that but reality is that takes you down to this tiny population and that's where it's going to change so I think across the world and we had a fantastic talk about pgta and how it should be evaluated and how to do it well from Richard that's what's going to transform when people start doing this immunological investigations and Angie's told you know how they do it in reality it's going to be individualized but in reality if you take Stephen's kind of estimates it's going to be after two or three euploid embryo transfers that's the population we're going to be studying in. I'm going to push back I'm not just I'm not just asking questions of the pro side but Dr. Cooper is there so you're on the con side but is there ever a time where you would do an immunologic evaluation for implantation failure yes for recurrent we're not talking rpl we're talking recurrent implantation failure yes and I think that's that is that is the fundamental problem here because we're we have to ask what and I know we're coming there but and we have to ask what what do we even are going to test for and what we're going to do with the results I always say if you're going to order a test know what you're going to do with the results and and those two next questions are probably the more difficult ones I think and so I agree with what Dr. Nelson just said that you know we really across the world have to agree upon a definition and the best way to do it is probably two or three euploid transfers but what are we going to order and and there are reproductive immunologists out there that are going to do a many many many thousand dollar workup and what are we going to do with those results and I think we have to treat the patient in front of us we have to look at maybe their history of autoimmune disease and sometimes I will look further into that but I will be very honest with them about the lack of data which is what we're debating on what test to even order and what to do with those results if I can just intervene I would say ask them their shoe size it's just like this immune stuff it doesn't mean anything and it can't direct treatment and it's free so that's what I would do so I'd rather spend my money on Valentino's I will so not to respond directly but wait a minute I just recently saw a patient and she had no history of autoimmune disease and she had a curious endocrine pattern that where she had a high LH normal FSH high AMH low testosterone and she'd undergone a couple of IVF cycles in which she got a total of one oocyte and because they all everything else arrested during development and I said you know maybe we ought to look for autoimmunity because she had had a baby about five six years prior without any trouble at all and I said something's acquired it's not genetic probably and and so I said let's look for some markers of autoimmunity and it turns out she had anti-adrenal antibodies and we and and as you know those cross-react with anti-fecal antibodies sometimes and and so we gave her prednisone and I heard from her doctor just during this meeting that she got 40 oocytes but it's not recurrent implantation failure I think that's this is autoimmunity right you said when would I this is recurrent implantation failure and she didn't have that all right so you're asking when would I check autoimmunity in recurrent issue failure yes sir ah well that's a different question he's not going to answer that he's going to hand the microphone I mean I agree he's going to take quite strongly that that look if we put back embryos a euplate embryo and it's 60 percent chance of implantation 40 percent chance something's going wrong right and if we do that over and over again well for god's sakes we ought to do something different and you know what should we do different we could we could argue what should we test for we could argue but I think we would agree that some different therapies are in order so I guess the next question you I couldn't have planted that better is what is your go-to immune therapy and what are the data behind that and there's a lot if you read the paper it covered heparin tnf alpha inhibition ivig intralipids aspirin steroid so there's a lot to choose from when you're thinking that you want to modulate the immune system dr balsos are there a few that really stand out in your mind as kind of being the most useful and when would you use them looking at figure one in the paper and also taking into consideration side effects adverse events and cost baby aspirin um and heparin sub-q heparin and if you look at b the total 95 percent confidence interval is 1.55 and it barely touched crosses one so I think that looks really good for our fellows in the audience but if you add but if you add the corticosteroids it's 1.29 which is amazing right and then do you care to comment on the statistics of that and intrauterine gcsf in our group intrauterine neupogen it's very easy to do and in here it clearly shows in this meta-analysis in that the confidence interval is 1.52 and that one didn't cross one but I think intralipids and and sub-q and sub-q are also other considerations what do you think so I'm dying to know as the fellow on the panel if I came to my oral boards exam and I backed it up with this data and I said I'm going to give all my patients aspirin who have had a failed transfer in the past I may start heparin as well and I cite this meta-analysis systematic review how would that go over that has to be answered by a non-board examiner I take the well Scott's from the UK so I've never done a boards exam so what I'd say is okay tell me where the point estimate is yeah and actually how does that point estimate how would that shift right because often what you find with bigger studies is the point estimate doesn't always shift the point estimate stays approximately the same and the confidence intervals get smaller so you and I would be having a super nuanced discussion about point estimates and be able to interpret it and actually it's not the p-values and as I said have you read the American Statistical Association of p-value statement because actually it's not about p-values anymore it's about the point estimate and kind of what's the direction effect so that's how we'd be having a conversation yeah but you're right I can understand why you might be saying okay how would it pan out with others because Stephen might be examining no I'm not a board examiner but but considering the side you're on I think you're in trouble already in the board exam so um I mean there was a recent randomized control trial on scratch it's obviously not included in this meta-analysis that showed a range that was oh just barely crossed one and it had it over a 1.2 fold benefit and there were some considerations as to why that was a multi-center trial was a Dutch trial done very rigorously and and you know um for those 20 benefit I mean if you could get 20 better IVF than than your competitors you'd be doing all right Dr. Scott I want to ask you to go through the mental exercise let's say you happen to be sitting on this side and you had immune therapies at your disposal and you had a patient in front of you with recurrent implantation failure what does your counseling look like for that patient when you're trying to decide you may be a good candidate for this this is how I would evaluate you for it and this is how I would choose a therapy for you unfortunately we don't have a lot in our armamentarium to manage recurrent implantation failure and one reason to try to get a more consistent definition I would just say listen to everything that Dr. Young told us over the last couple of days is specifically so we can learn more about it but as of today I don't do all those immunologic tests I do do some of the things that Dr. Beltz has mentioned I really try to make sure their uterus is normal if they've got any evidence of abnormality we do HSTs we even frequently I'll do it I'll do a scope just to really look because I really don't want to miss something and occasionally I found that I had missed something so that's just anecdotal but that's but that's you know our task today is immune therapies when you have somebody with recurrent implantation failure you have to go back and think about it in the biologic system way which is in each transfer what contributes to the outcome most and I think that while we might disagree on the proportions most people would still say the embryo has the most to do with reproductive outcomes and I think that when you do that when I'm going to tell that patient that I'm going to do something different the reality is or do what seems to them to be the same thing again it's something completely different because I'm putting a completely different embryo in their individual cavity so that's what I'm changing I'm changing the embryo which is the single largest and most critical factor and so beyond that I think it is extremely important that we resist the temptation of doing something because we don't know what to do and I'm only pointing myself there I don't know what to do with those patients if your endometrium is perfect you've got a 10 type 1 endometrium mid cycle your progesterone levels are awesome we've done everything we know how to your uterus your tubes are in great shape and everything looks just just right I don't I don't have anything to add except to transfer another uterus another one and so in reality I don't do all of that I resist that temptation because I don't think it's fair I think it really creates a false expectation on the part of the patient oh you gotta you gotta do something she keeps failing and she's looking to you to try something you take paul proteus data and took the people who failed three euploids and you do a fourth euploid transfer right you're already up to 92 point whatever it was I apologize I remember eight I think but 92 point something percent have delivered and now you're in that last recalcitrant seven and a half percent which is lower than the 10 estimate for if for the that was published in reproduction last year guess how many deliver changing nothing but putting a different embryo back 60 percent deliver you still have those people that and you failed and failed you take that embryo put it in a gestational carrier and they get pregnant well actually you don't know because you can't put the same embryo in a gestational carrier but this it doesn't matter by the way if you put in a gestational carrier the pregnancy rate 60 it's the same but this one's batting zero and but after batting zero the implantation rate 60 if you put it in a gestational carrier it's 60 as you said you're either it's binary you're either pregnant or not if you use donor eggs in her and put them back now you're saying gosh it's not an embryonic factor so you would expect it to do very poorly they do great so it still doesn't get pregnant we we have those patients we all have those patients i'm sure so at some point you got to do something different i i really i i think i would love to do something different i think it uh i think we have to resist though doing things that are not uh that are not um arguably beneficial we do that all day what i don't there's a lot of stuff that is not proven but where's he death taxes and i think pretty much everyone's going to die i think there's evidence for that um the rest of this are about percentages and when you have that couple in front of you there is the possibility that the immune system is acting up and doing things that do not cost a lot that are not that risky and maybe might help at some point is worth giving that a chance are you at all worried about misleading them and creating false hope oh that part is really an important point thank you for bringing that up and i 100 agree that you say we are at this juncture we don't know why this isn't working and we are spending thousands of dollars thousands of hours and these are some things that might be a consideration for you we don't know but it might help it may not what would you like to do but you've basically endorsed it by offering it you've endorsed it by offering it right that's not neutral but but what are you endorsing do you think that detection of antiphospholipid persistent antiphospholipid antibodies which might cause a blood clot in early pregnancy do you think that that is a terrible test to do but do you test for those on everyone of course not but on recurrent implantation failure or recurrent pregnancy loss i might do so recurrent pregnancy i think the presence of antiphospholipid antibodies in the absence of a thrombotic event doesn't prognosticate much dr cooper can you elaborate no it's lower it's a lower chance so so if you had a patient that had persistent immunoglobulin igg antibodies against you know there were antiphospholipid antibodies just floridly positive you would not offer her heparin to start in her ivf cycle and to finish and and to continue into early pregnancy we do not we do not and i i would love to see the paper that shows that that helps remember that even in the when the people were looking in antiphospholipid antibodies and there were two large international symposium the second one was in auckland and that's where they said now three first trimester losses could be counted as part of the syndrome yeah and that's obviously way downstream from implantation and if you look and they go through and they're very honest what was their level of evidence they actually say in the committee statement that there is no evidence to support this whatsoever it was just the opinion of those attending but but here's no evidence there's no data there's no reason to believe it's true so so somebody with a current pregnancy loss which is an indication for a very different issue we're talking about recurrent implantation we are failure i think we're talking about both fertility um but but if you it seems to me that the risk of vte and a patient who's going to be pregnant who's going to have high estrogen levels far outstrips the risk of of low-dose heparin in in early pregnancy and and it's not going to be for someone who has antiphosphatidyl ceramide or whatever you know it's going to be the patient who has true antiphospholipid antibodies and they're persistent those patients the the risk of an immunotherapy like heparin is low and their chance of vt and if they get that is elevated for sure now how much you can argue we have the benefit of having someone who doesn't practice in the united states and perhaps is unburdened a little bit by what we do in the u.s you have the hfea in the uk how do they guide your practice as a pro immunotherapy practitioner no i'm a pro i'm on the side of the debate that's a slight difference okay so let's just be clear uh we've had some conversations in advance of this uh the reality is so the hfea is a government regulator because in the uk ivf is licensed by a parliamentary act and they were very conscious that patients were being potentially exploited by clinics for a whole series of add-ons now those add-ons are essentially things that they will buy in addition to a classic ivf cycle so and they can range from a time-lapse incubator if it's being charged extra they can be right you know pgta is classed as an add-on uh and immunological investigations and treatments are also classed as an add-on and they came up with a very simple traffic light system which was does this in robust rcts improve the chance for the majority of patients of them having a live birth and actually you know immunological therapies has a red traffic light against it now you'll be surprised to hear that pgta also has a red traffic light against it as well despite the dominance of that within you know the pro side of this you know table as well so the reality of it is that these are you know recognized as being potential add-ons that are generally will not improve the majority of people's live birth rates but they accept that there is certain subpopulations that may do that and on monday before i flew to chicago the hfea met and i'm a member of that in terms of the scientific advisory committee that was on it and what they were interested in is they've always been relying on rcts and we had jack wilkinson who's written lots of papers as well on it as being the other part of it and what the end conclusion was and what they're going to recommend to the hfea overall board is that we actually look at etiological triangulation in terms of other forms of evidence for rcts so when you think about etiological evident triangulation it's not just all about rcts and it's hierarchy because you can see that you can do really bad meta-analysis and that's what i'm trying to show you this is a bad meta-analysis the reality of it is that actually we need to think about other ways of being able to kind of triangulate on those effects and you know you can think about observational studies and richard talked about how it's hard to do rcts actually it's super easy for richard to do rcts in medicine because he could do a step wedge rct across his group yeah and his group's massive so very quickly he could do a really adequately powered rct on any of these studies yeah but at present the hfea has got a red traffic light against immunological therapies and testing and so it's not advocated at all in the uk um thank you so we are gonna we're getting close to wrap up time and so each one of our panelists is going to have about 60 seconds or less to share with us the couple main points that you'd like the audience to take away dr sacks great well i'm glad to have this opportunity because there were two comments i wanted to rebute rebuttal a little earlier one is to dr young in terms of antiphospholipid antibody syndrome although these studies did look into those five autoimmune studies that are included here looked into positivity they didn't look at the quantifying ability and i can't can't in my gut understand how a 40 year old woman with tpo greater than 100 can be created equal with a 30 year old whose tpo levels are just detectable and so i think that again it goes into the quality of the evidence included here and we need really concise definitions for patients included in these studies additionally i think the point that dr scott brought up about gestational carriers is something that we really need to involve in that shared decision making with our patients when we say gestational carriers have phenomenal pregnancy rates and we know that the the hla allotyping of those embryos are different than their immune systems and yet they still do incredibly well so i think that's what we need to focus the conversation on going forward thank you i would say my points would be the immune system no doubt matters it's fundamentally important in establishing pregnancy and maintaining pregnancy and we need more research in this area probably the most profound immunologic things we all use is progesterone really and because it it modifies the th1 th2 mediated response we don't even agree on how much to give and how long to give it in the decidua the uterus the big immunologic protective factor everything else we often throw the kitchen sink at patients that patient in front of us is very vulnerable we want nothing more for that patient to have a healthy pregnancy but we might say sprinkle this purple powder on your head and if it works that time it might be that purple powder we can't figure out sometimes what we're doing and what we're not doing and the question at hand is are the current immunologic therapies safe and effective some of them are probably safe but is effectiveness data there it's not currently and we need to get to a point where we understand even what tests to order and what to do with those results right now we're not there yet well i i would just say ditto um that was really an excellent an excellent summation of where we are in all of this again no one believes that the immune system is unimportant and no one believes that the immune system is not involved in reproductive failure i do believe that the the bulk of the evidence and we didn't go through all of it today and i apologize um is more for failure of pregnancies post implantation than impairing the implantation process and so by um just limiting the discussion today to recurrent implantation failure kind of the con side maybe we had a little home court advantage by not acknowledging the what is obviously clinically important which would be the entire gestation but at this point i think it it falls on all of us to resist the temptation to to do something because we don't know what to do and if so i think we should really be careful about using these therapies which do have some risk and at times can involve very substantial expense dr scott maybe we'll go the other way he's he's our he's our closer so um resist the temptation to not do anything resist the temptation to try to do everything you can to optimize that chance and with transparency using medications that are low cost and with possible benefit we encourage you to think about using immunotherapy with subfertile women who have failed implantation we know that the immune system can be a problem if we can identify those patients who we are we think are highly likely to have altered immunity i would argue for this panel that this is the group that we need to apply immunotherapy when you read a meta-analysis just think about is this done in someone's bedroom late at night because the reality of it most of it is yeah and you can do it and you can churn it out and then it's either going to be pushing you one way or it's pushing you the other and actually what you need to do is go back and look at the original studies and think are these relevant to me today and what i've said to you was there's of 53 studies seven were from the U.S. and actually most of these are not relevant to you because they were before you current medicine and your euploid embryo transfers not a single one of them is about you point so when we think about it what we're trying to show you today is a much more refined way of thinking about these therapies and we show you a diagnostic pathway for them and then it's in the context of that Richard has outlined how we might take science forward but that's how we need to work with it are these relevant and where can we draw the evidence from from other systems whether it be some Mandela and randomization natural experiment designs stepwise through cohort studies or whatever observational studies with you know confounding adjustments as best we can that's when you need to think about it so actually don't just think that someone's created a meta-analysis that that's the top grade of evidence far from it and actually please think about the patient you've got in front of you and how that might be impacted i can't think of a better way to end i wanted to thank our panelists for having to take positions that they may not necessarily agree with so thanks to both sides for that i also want to thank my co-host dr feinberg for joining us live at the midwestern reproductive symposium international annual meeting i want to encourage everyone who's participating in this debate here today to also check in our next debate where we're going to be co-hosting an event on thursday june 16th just soon with the british society for gynecologic endoscopist we're going to be talking about non-invasive diagnosis of endometriosis as the next hot topic especially as we're doing less and less reproductive surgery which pains my reproductive surgery heart but it allows us to get information that may help our patients and move the ball forward for them so with that we'll conclude unfortunately we don't have time for questions because we ran out of time today but thank you to everyone in the live audience thanks again to the panelists and all of you who are watching online good night
